Denis G. McDevitt

Clinical pharmacologic observations on atenolol, a beta‐adrenoceptor blocker

The effects of oral and intravenous administration of atenolol were studied in healthy volunteers. The oral administration of aseries of single doses of atenolol reduced an exercise tachycardia. After a 200‐mg dose, the effect on an exercise tachycardia was maximal at 3 hr and declined linearly with time at a rate of approximately 10% per 24 hr. The peak plasma atenolol concentration occurred at 3 hr and thereafter declined exponentially with time with an elimination half‐life of 6.36 ± 0.55 hr: 43 ± 3.9% of the dose was excreted in the urine within 72 hr. There was a correlation between the reduction in an exercise tachycardia and the logarithm of the corresponding plasma concentration. The intravenous administration of atenolol reduced exercise tachycardia with a signi(icant correlation between effect and plasma concentration. After 50 mg intravenously, 100% of the dose was recoveredfrom the urine, ami the clearance was 97.3 ml/min. Comparison of AUCo→x after oral and intravenous administration of 50 mg showed the bioavailability to be 63% after oral drug. Repeated oral administration of atenolol 200 mg daily either as a single dose or in divided 12 hourly doses for 8 days maintained reduction of an exercise tachycardia of at least 24% during the period of drug administration. The plasma elimination half‐life, area under the plasma concentration‐time curve, and peak plasma concentration after 200 mg atenolol were not changed by chronic dosing for 8 days.

Influence of intrinsic sympathomimetic activity and cardioselectivity on beta adrenoceptor blockade

Dose‐response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized exercise test and percentage reduction in exercise heart rate (EHR) as the index of drug effect. The dose‐response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor‐blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor‐blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetic activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor‐blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprellolol was given after sotalol or oxprenoloi, or practolol was given after sotaloi or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenoiol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenoloi or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the dose‐response curves with exercise.

Adrenoceptor Blocking Drugs: Clinical Pharmacology and Therapeutic Use

SummaryAdrenoceptors can be divided into α-receptors, whose stimulation results in excitatory responses, and β-receptors which are mainly responsible for inhibitory responses plus cardiac stimulation. β-Receptors can be further subdivided into β1-receptors in the heart and β2-receptors elsewhere. Drugs are now available which selectively antagonise responses mediated by both α-and β-adrenoceptors.α-Adrenoceptor blocking drugs have been known for many years. Some are competitive inhibitors (e.g. tolazoline and thymoxamine); others (such as phenoxybenzamine) produce non-equilibrium blockade once their effect is established; still others (prazosin) appear to block post-junctional α-receptors selectively and consequently exert an antihypertensive effect without tachycardia. The effects of α-adrenoceptor antagonists in therapeutic doses are seen chiefly in the cardiovascular system: if the patient changes from the supine to the standing position or if there is a marked reduction in plasma volume, a marked fall in blood pressure occurs with reflex tachycardia. α-Adrenoceptor blocking drugs have additional potent pharmacological properties, some of which profoundly impair their usefulness and increase toxicity.The principal usefulness of α-adrenoceptor antagonists is in the management of phaeochromocytoma — preoperative preparation, prevention of paroxysmal hypertension during surgery and prolonged treatment of cases not amenable to surgery. Occasionally, combined α-and β-adrenoceptor blockade may be required, but the α-blockade must always be established first. α-Adrenoceptor blocking drugs have never been widely used in the management of essential hypertension due to reflex tachycardia and a tendency for their hypotensive effect to wear off. However, the newer drugs prazosin and indoramin do not appear to share these disadvantages and may establish a greater therapeutic role. α-Adrenoceptor antagonists are also used in the treatment of shock and peripheral vascular insuffïciency, although evidence for their efficacy in the latter is sparse except where decreased blood flow is due to spasm of the vessels (e.g. Raynaud’s phenomenon). Recently, phentolamine and prazosin have been shown to be useful in some patients with refractory congestive cardiac failure.β-Adrenoceptor blocking drugs are competitive antagonists which have enjoyed increasingly widespread clinical usage during their 10 year history. There are now a number of drugs of this type available, all of which competitively block β-receptors. They differ in terms of their additional properties, such as membrane stabilising activity, partial agonist activity and cardioselectivity, but it would appear that of these, only the latter is of clinical importance. Cardioselectivity refers to the ability to block cardiac β1-receptors selectively without blocking β2-receptors in the bronchi and blood vessels. Atenolol and metoprolol have been shown to be cardioselective drugs and these drugs should be prescribed in patients with obstructive airways disease and insulin-dependent diabetes in preference to the other non-selective drugs. However, all β-adrenoceptor antagonists should be used cautiously in these patients and in those with a previous history of or evidence of incipient congestive heart failure, as potentially they may cause serious adverse reactions. The maximum danger period exists during administration of the initial low doses in these patients because this represents the maximum interference with the sympathetic environment. If harm does not ensue in this period, further increases in dose are less likely to cause problems.β-Adrenoceptor antagonists were originally prescribed for angina pectoris, cardiac dysrhythmias and phaeochromocytoma. Subsequently, they have been found to be of use in hypertension, following myocardial infarction, in hyperthyroidism, anxiety states, migraine, hypertrophic obstructive cardiomyopathy and drug addiction withdrawal syndromes. Their use is also being investigated in a number of other conditions.β-Adrenoceptor blockade does not appear to explain satisfactorily their efficacy in all of these circumstances. The role of β-adrenoceptor antagonists prophylactically in angina pectoris is clearly established and is an effective alternative to coronary artery bypass surgery in many patients. Recently, it has also been suggested that these drugs may reduce mortality in patients following an acute anterior myocardial infarction. β-Adrenoceptor blocking drugs are amongst the drugs of first choice, if not the drugs of first choice, in the treatment of hypertension, as they combine satisfactory efficacy with low toxicity. In addition, they can be used to good effect in combination with diuretics, vasodilators or other antihypertensive drugs.Various cardiac dysrhythmias can be successfully treated with β-adrenoceptor antagonists. In hyperthyroidism, these drugs ameliorate the peripheral manifestations of the disease: they can be life-saving in hyperthyroid crisis, and can be used instead of conventional antithyroid drugs in the preoperative preparation of patients for thyroideciomy or following radioiodine therapy. The somatic symptoms and signs of anxiety neurosis are improved by β-adrenoceptor blockade and the frequency of occurrence of migraine headache has been found to be reduced by the prophylactic use of propranolol.Thus β-adrenoceptor blockade has a much wider role in the management of disease in man than has α-adrenoceptor blockade. The former have achieved great importance in a short time.

Central effects of beta‐adrenoceptor antagonists

The central effects of atenolol, a cardioselective beta‐adrenoceptor antagonist, were investigated in six healthy men. Two flash‐fusion threshold (2FFT), simple reaction time (SRT), digital copying (DCT), symbol‐digit modalities (SDMT), and Gibsons spiral maze tests (GSMT) and mood rating scales for tension, alertness, depression, detachment, and anxiety were used. Each subject took 50, 100, 200, and 400 mg atenolol and identical placebo orally in a randomized, double‐blind, crossover study and the psychomotor tests were performed at 0, 2, 3, 5, and 8 hr. 2FFT was prolonged at 3 hr after all doses and at 2 and 5 hr with 100, 200, and 400 mg. The maximum effect was achieved with 200 mg and mean 2FFT correlated with mean plasma atenolol concentration. SRTs were prolonged after all doses at between 2 and 5 hr. The DCT and the retest gain of the SDMT were both lower than after placebo at 2 hr with 100, 200, and 400 mg. The time taken to perform the GSMT was not altered by active drug, but the number of errors was lower at 2 hr with 100 and 200 mg. The self‐rating mood scales showed a subjective decrease in tension 2 hr after 400 mg. The results show that atenolol exerts central effects in man.

Blood levels of practolol after oral and parenteral administration and their relationship to exercise heart rate

Blood levels of practolol after oral and parenteral administration were determined in normal subjects, and the effects of each dose on the heart rate induced by strenuous exercise were measured. Oral practolol was rapidly absorbed and produced peak blood levels in 1 to 3 hours. Between 2 and 7 hours blood levels varied little more than twofold either within or between subjects. The half‐life of practolol in blood was 10 to 11 hours. Practolol100 mg was the minimum dose to produce near maximum blockade at 2 hours; maintenance of this effect for 24 hours reqUired 400 mg. Near maximum blockade was produced as long as a blood practolol level of 1.0 to 1.4 µg per milliliter was maintained. There was a correlation between the logarithm of the blood practolollevel and the percentage reduction of exercise heart rate. Practolol 40 mg and 80 mg intravenously initially achieved near maximum blockade associated with blood practolol levels above 1.0 p.g per milliliter. The effects and blood levels fluctuated during the first 7 hours. Intramuscular doses up to 40 mg failed to produce near maximum blockade; higher doses were precluded by pain at the injection site.

Digitalis: Its Place in Modern Therapy

Digital is was used successfully, for the first time, in the treatment of dropsy by W illiam Withering more than 200 years ago. Failure to unders tand properly how it worked, or in which clinical situations it might be given, resulted in its abandonment as a therapeutic agent for more than 100 yean. However. since the beginning of the century digitalis has been rediscovered as a drug which could control atrial dysrhythmias and which was of value in the management of card iac failure . Digitalis is still regarded not only as one of the oldest drug s available for the treatment of cardiac disease but also as one of the most valuable. Recently certa in aspects of its usefulness have again been questioned , most notably its efficacy in the long term management of card iac failure in patients with sinus rh ythm Oohnsto n and McDevitt , 1979; McHalTte et al., 1978). Digital is was adm inistered originally as a preperation of powdered leaf. This has now been superseded by synthetic cardiac glycosides which are more easily sta ndardised. In the following discuss ion, th is group will be referred to as a whole but the character istics of individual glycosides will be mentioned subsequently . I . Main Clinical Indications / or Use 0/ Cardiac Glycosides (Table n

Effects of thyroid dysfunction on propranolol kinetics

Propranolol kinetics was studied in six hyperthyroid and six hypothyroid patients who received single oral and intravenous doses of propranolol when they had thyroid dysfunction and again when they had become euthyroid. Change in thyroid status from hyperthyroid to euthyroid produced no change in the elimination half‐life (t½) of oral propranolol (3.2 ± 0.5 to 4.1 ± 0.7 hr), the oral clearance (38.4 ± 7.3 to 27.4 ± 2.4 ml/min/kg), the elimination t½ of intravenous propranolol (2.5 ± 0.3 to 3.5 ±0.7 hr), and the apparent volume of distribution (4.8 ± 0.4 to 3.8 ± 0.5 l/kg). The systemic clearance of propranolol, however, was greater when the patients were hyperthyroid (20.8 ±2.5 ml/min/kg) than when they had become euthyroid (11.7 ± 1.7 ml/min/kg). The elimination t½ after oral propranolol was longer in the hypothyroid (3.7 ± 0.5 hr) than in the euthyroid state (2.0 ±0.1 hr). No other changes were observed in the kinetic parameters measured when these hypothyroid patients had become euthyroid. Adequate β‐adrenoceptor blockade in hyperthyroid patients may require higher propranolol dosage than expected.

Why measure plasma theophylline concentrations

SummaryStudies have been carried out with a number of theophylline preparations, both in normal subjects and inpatients with obstructive airways disease, to obtain information about plasma theophylline concentrations. With some of the formulations studied, ‘usual’ or recommended doses failed to produce plasma theophylline levels within the optimum range of 10 to 20 μg/ml. Because of the large inter-individual variation between patients, it would appear that dose requirements with different drugs should be carefully monitored and that regular plasma theophylline concentration measurements should be considered in patients with obstructive airways disease, particularly when clinical management is difficult.

Erythrocyte cation transport and age: Effects of digoxin and furosemide

The uptake of rubidium 86 (86Rb) by human erythrocytes was measured at various ages. Effects of digoxin and furosemide on this process were examined and, in the case of digoxin, related to its numbers of specific cellular binding sites. There were no significant effects of age on absolute cellular Rb uptake, digoxin‐sensitive Rb uptake, or numbers of cellular binding sites for digoxin, but the ability of digoxin to inhibit digoxin‐sensitive 86Rb uptake increased with age. The ability of furosemide to inhibit digoxin‐insensitive 86Rb uptake did not change with age. Results suggest a dynamic contribution to altered sensitivity to digoxin in elderly persons.